Elevated levels of insulin-like growth factor II (IGF-II) and IGF- II mRNA are found in the plasma and tumor of adults with tumor of mesenchymal origin and in children with Wilms tumors (Wt). This tumor is thought to have arisen during the reinitiation of nephrogenesis by metanephric blastema and is found in an non- inheritable or variant forms that differ in their morphology, proliferation rate, metastatic potential and levels of expression of the IGF-II gene. It has been suggested (3) that macro-or micro- alterations of a repressor gene ie, WAGR, in chromosome brand 11p13 could stimulate IGF-II synthesis and it, in turn would stimulate the replication of the incompletely differentiated Kidney cells. Alternatively the over expression of the IGF-II gene in WTs could be a manifestation of one of a number of biochemical events that accompany normal nephrogenesis. Evidence is presented that a) different molecular weight forms of processed IGF-II, are found in fetal tissues, b) they have different biological effects and C) their specificity changes presumably because of changes in the IGF- I receptor. Thus, there are three requirements for normal nephrogenesis in the embryo and abnormal nephrogenesis in the WT; a source of IGF-II, the right processed forms of IGF-II and IGF-II and IGF-I receptors of a changing phenotype that modulate IGF-II's mitogenic and differentiating effects. If the variant morphological forms of WT are representative of the stages of kidney organogenesis that have been inappropriately terminated, then I predict that their growth factor and receptor specificity requirements will be the same as embryonic kidney cells at the same stage of development. I propose to use the variant forms of this embryonic tumor to evaluate the role of IGF-1 and the IGF-1 receptor in tumorigenesis; 1) by measuring the quantity of IGF-1 and the two Mr forms of IGF-11 and fetal IGF-binding protein in a) the serum and in b) the extracts of normal kidney, nephroblastomatosis nodules, and tumors of defined morphology from children with WTs, and in fetal Kidneys of gestational age 9 to 19 weeks; 2) by comparing their levels of expression and mRNA size and the sites of their synthesis by in situ hybridization procedures; 3) by characterizing nephroblastomatosis of development. I propose to use the variant forms of this embryonic tumor to evaluate the role of IGF-II and the IGF-I receptor in tumorigenesis; 1) by measuring the quantity of IGF-I and the two Mr forms of IGF-II and fetal IGF-binding protein in a) the serum and in b) the extracts of normal kidney, nephroblastomatosis nodules, and tumors of defined morphology from children with WTs, and the fetal kidneys of gestational age 9 to 19 weeks: 2) by comparing their levels of expression and mRNA size and the sites of their synthesis by in situ hybridization procedures, 3) by characterizing the receptors on membranes prepared from these tissues with respect to their affinity and specificity for IGF-1 and the two Mr forms of IGF-11, their structure, ligand -stimulated protein kinase activity, and hetrotetramer formation, and 4) by characterizing IGF-I and -II receptor mRNAs.